The central nervous system (CNS) relies in part upon dopaminergic neurotransmission for its full and efficient operation. Therefore, agents that act as ligands at dopamine receptors are likely to have CNS activity. Use of such agents may be of great value in CNS research or, potentially, as therapeutic agents.
The significance of certain tetracyclic compounds as dopamine agonists has been described by M. R. Michaelides et al. in WO94/22858 (corresponding to U.S. patent application Ser. No. 08/209,982, filed Mar. 17, 1994, which is incorporated herein by reference). In addition, other tetracyclic compounds such as dihydrexidine, a trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine, and its 2-methyl derivative have been identified as potent and selective dopamine D1 agonists (cf., D. E. Nichols, U.S. Pat. No. 5,047,536, issued Sep. 10, 1991, Nichols, R. B.; Mailman, R. B. WO 93/24462, published Dec. 9, 1993 and Brewster et al, J. Med. Chem., 33:1756-64 (1990)).
Obtaining either of these tetracyclic moieties in chiral form has not been easy, however. Dihydrexidine is known to possess within its fused ring system the trans-configuration of fused rings which corresponds to the structure of the powerful dopamine agonist, 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (ADTN), which itself possesses greatest activity in its chiral (R)-(+)-isomeric form (see P. Seeman, Pharmacol. Rev. 32:2:229 (1980)). Knoerzer et al. (J. Med. Chem., 37:2453-60 (1994)) have now reported the resolution of the pair of chiral isomers of dihydrexidine and confirm that the 6aR,12bS-(+)-isomer is the more active pharmacologically. They also showed that the 6aS,12bR-(-)-isomer is inactive in an adenylate cyclase assay.
The synthesis of dihydrexidine as reported by Nichols and Brewster (cited above) generates the racemic pair of trans-isomers (6aR,12bS and 6aS,12bR) and, therefore, represents an inefficient preparation of the active chiral isomer (50% maximum theoretical yield of the desired isomer). In addition, the chiral products of Michaelides et al (cited above) are also prepared by resolution of the racemate, and therefore their synthesis also has a theoretical maximum 50% efficiency.
We have now found, and the present invention describes, a process for preparing chiral isomers of dihydrexidine and, particularly, of certain other tetracyclic dopaminergic compounds as described above.
This process begins with an improved synthesis of the known chiral starting material ((2R)-4-(3,4-dimethoxyphenyl)-2-((trifluoroacetyl)amino)butyric acid, CAS Reg. No. 97403-65-1, compound (2) in the process described below), and proceeds through a series of chiral intermediates, thus assuring the chiral purity of the final product.
For the synthesis of compound (2), Nordlander et al. (J. Org. Chem, 50:3619-3622 (1985)) utilized methylene chloride as the solvent in the initial condensation step, and he reported a 55% yield. This yield could not be obtained in our hands (see Examples 7-9 and Table 2 below), and we have found that the use of nitromethane in place of methylene chloride as the solvent allows for improved and reliable yields.
Literature searches have shown that the intermediates below identified by the numbers 3, 5, 6, and 7 are novel compounds. The ability to maintain chirality within step (b) below was earlier confirmed by T. L. Cupps et al. (J. Org Chem50:3972-79 (1985)) and M. R. Angelastro et al. (J. Org. Chem., 54:391 3-16 (1989)), among others, who reported that alpha-amino acids such as phenylalanine, for example, may be converted into the chiral N-methoxy-N-methyl-amides or isoxazolidides thereof.
The subsequent ability to condense chiral amides with organometallic ligands, as in step (c) below, has been reported with various ring systems such as indole (M. P. Moyer et al., J. Org. Chem., 51:5106-10 (1986)), tetrahydropyridines (J. S. Ward et al., J. Hetero. Chem. 27:1709-12 (1990)), dimethoxyisocoumarins (C. N. Lewis et al., Synthesis-Stuttgart, 11:944-946 (1986)), and substituted thiazoles (J. J. McNally et al., J. Hetero. Chem., 29:247-250 (1992)).
The reduction of chiral alpha-keto amines to the corresponding alpha-hydroxy amines, as in step (d) below, is known. Also known is cyclization and dehydration of suitable alcohol compounds to form ring compounds, as in step (e) below, and the condensation of an amine with an intramolecular carbon atom with the assistance of a suitable leaving group, as in step (f) below.
However, there is nothing in the individual references cited, nor in other literature, taken together with such references, to suggest the process of the present invention.